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. 1995 May 1;181(5):1643–1651. doi: 10.1084/jem.181.5.1643

Intermediate steps in positive selection: differentiation of CD4+8int TCRint thymocytes into CD4-8+TCRhi thymocytes

PMCID: PMC2191983  PMID: 7722444

Abstract

The differentiation potential of putative intermediates between CD4+8+ thymocytes and mature T cells has been examined. Such intermediate populations were sorted, in parallel with CD4+8+ thymocytes, from three types of C57BL/6 mice: major histocompatibility complex (MHC) class II- deficient mice, mice transgenic for an alpha/beta T cell receptor (TCR) restricted by class I MHC and normal mice. The sorted populations were then transferred into the thymus of nonirradiated C57BL/Ka mice differing in Thy 1 allotype, and the progeny of the transferred cells were analyzed 2 d later. Surprisingly, with all three types of donor mice, a major proportion of the CD4+8intTCRint-derived progeny were found to be CD4-8+TCRhi cells, thus delineating a new alternative pathway for development of the CD8 lineage. In contrast, the transfer of CD4int8+TCRint thymocytes produced CD4-8+TCRhi cells but no significant proportion of CD4+8-TCRhi cells, suggesting that there is no equivalent alternative pathway for the CD4 lineage. The results negate some of the evidence for a stochastic/selective model of lineage commitment, and point to an asymmetry in the steps leading to CD4-8+ versus CD4+8- T cells.

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Selected References

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  1. Baron A., Hafen K., von Boehmer H. A human CD4 transgene rescues CD4-CD8+ cells in beta 2-microglobulin-deficient mice. Eur J Immunol. 1994 Aug;24(8):1933–1936. doi: 10.1002/eji.1830240834. [DOI] [PubMed] [Google Scholar]
  2. Bendelac A., Killeen N., Littman D. R., Schwartz R. H. A subset of CD4+ thymocytes selected by MHC class I molecules. Science. 1994 Mar 25;263(5154):1774–1778. doi: 10.1126/science.7907820. [DOI] [PubMed] [Google Scholar]
  3. Benoist C., Mathis D. Generation of the alpha beta T-cell repertoire. Curr Opin Immunol. 1992 Apr;4(2):156–161. doi: 10.1016/0952-7915(92)90005-y. [DOI] [PubMed] [Google Scholar]
  4. Bhattacharya A., Dorf M. E., Springer T. A. A shared alloantigenic determinant on Ia antigens encoded by the I-A and I-E subregions: evidence for I region gene duplication. J Immunol. 1981 Dec;127(6):2488–2495. [PubMed] [Google Scholar]
  5. Borgulya P., Kishi H., Müller U., Kirberg J., von Boehmer H. Development of the CD4 and CD8 lineage of T cells: instruction versus selection. EMBO J. 1991 Apr;10(4):913–918. doi: 10.1002/j.1460-2075.1991.tb08024.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Borgulya P., Kishi H., Müller U., Kirberg J., von Boehmer H. Development of the CD4 and CD8 lineage of T cells: instruction versus selection. EMBO J. 1991 Apr;10(4):913–918. doi: 10.1002/j.1460-2075.1991.tb08024.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chan S. H., Cosgrove D., Waltzinger C., Benoist C., Mathis D. Another view of the selective model of thymocyte selection. Cell. 1993 Apr 23;73(2):225–236. doi: 10.1016/0092-8674(93)90225-f. [DOI] [PubMed] [Google Scholar]
  8. Coffman R. L. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development. Immunol Rev. 1982;69:5–23. doi: 10.1111/j.1600-065x.1983.tb00446.x. [DOI] [PubMed] [Google Scholar]
  9. Crompton T., Ohashi P., Schneider S. D., Pircher H., MacDonald H. R. A cortisone sensitive CD3low subset of CD4+CD8- thymocytes represents an intermediate stage in intrathymic repertoire selection. Int Immunol. 1992 Feb;4(2):153–161. doi: 10.1093/intimm/4.2.153. [DOI] [PubMed] [Google Scholar]
  10. Crump A. L., Grusby M. J., Glimcher L. H., Cantor H. Thymocyte development in major histocompatibility complex-deficient mice: evidence for stochastic commitment to the CD4 and CD8 lineages. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10739–10743. doi: 10.1073/pnas.90.22.10739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Davis C. B., Killeen N., Crooks M. E., Raulet D., Littman D. R. Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes. Cell. 1993 Apr 23;73(2):237–247. doi: 10.1016/0092-8674(93)90226-g. [DOI] [PubMed] [Google Scholar]
  12. Davis M. M., Bjorkman P. J. T-cell antigen receptor genes and T-cell recognition. Nature. 1988 Aug 4;334(6181):395–402. doi: 10.1038/334395a0. [DOI] [PubMed] [Google Scholar]
  13. Guidos C. J., Danska J. S., Fathman C. G., Weissman I. L. T cell receptor-mediated negative selection of autoreactive T lymphocyte precursors occurs after commitment to the CD4 or CD8 lineages. J Exp Med. 1990 Sep 1;172(3):835–845. doi: 10.1084/jem.172.3.835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hogquist K. A., Jameson S. C., Heath W. R., Howard J. L., Bevan M. J., Carbone F. R. T cell receptor antagonist peptides induce positive selection. Cell. 1994 Jan 14;76(1):17–27. doi: 10.1016/0092-8674(94)90169-4. [DOI] [PubMed] [Google Scholar]
  15. Holmes K. L., Langdon W. Y., Fredrickson T. N., Coffman R. L., Hoffman P. M., Hartley J. W., Morse H. C., 3rd Analysis of neoplasms induced by Cas-Br-M MuLV tumor extracts. J Immunol. 1986 Jul 15;137(2):679–688. [PubMed] [Google Scholar]
  16. Houston L. L., Nowinski R. C., Bernstein I. D. Specific in vivo localization of monoclonal antibodies directed against the Thy 1.1 antigen. J Immunol. 1980 Aug;125(2):837–843. [PubMed] [Google Scholar]
  17. Kirberg J., Baron A., Jakob S., Rolink A., Karjalainen K., von Boehmer H. Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor. J Exp Med. 1994 Jul 1;180(1):25–34. doi: 10.1084/jem.180.1.25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Köntgen F., Süss G., Stewart C., Steinmetz M., Bluethmann H. Targeted disruption of the MHC class II Aa gene in C57BL/6 mice. Int Immunol. 1993 Aug;5(8):957–964. doi: 10.1093/intimm/5.8.957. [DOI] [PubMed] [Google Scholar]
  19. Ledbetter J. A., Herzenberg L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. doi: 10.1111/j.1600-065x.1979.tb00289.x. [DOI] [PubMed] [Google Scholar]
  20. Lundberg K., Shortman K. Small cortical thymocytes are subject to positive selection. J Exp Med. 1994 May 1;179(5):1475–1483. doi: 10.1084/jem.179.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Marodon G., Rocha B. Generation of mature T cell populations in the thymus: CD4 or CD8 down-regulation occurs at different stages of thymocyte differentiation. Eur J Immunol. 1994 Jan;24(1):196–204. doi: 10.1002/eji.1830240131. [DOI] [PubMed] [Google Scholar]
  22. Miceli M. C., Parnes J. R. Role of CD4 and CD8 in T cell activation and differentiation. Adv Immunol. 1993;53:59–122. doi: 10.1016/s0065-2776(08)60498-8. [DOI] [PubMed] [Google Scholar]
  23. Petrie H. T., Strasser A., Harris A. W., Hugo P., Shortman K. CD4+8- and CD4-8+ mature thymocytes require different post-selection processing for final development. J Immunol. 1993 Aug 1;151(3):1273–1279. [PubMed] [Google Scholar]
  24. Robey E. A., Fowlkes B. J., Gordon J. W., Kioussis D., von Boehmer H., Ramsdell F., Axel R. Thymic selection in CD8 transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage. Cell. 1991 Jan 11;64(1):99–107. doi: 10.1016/0092-8674(91)90212-h. [DOI] [PubMed] [Google Scholar]
  25. Robey E., Fowlkes B. J. Selective events in T cell development. Annu Rev Immunol. 1994;12:675–705. doi: 10.1146/annurev.iy.12.040194.003331. [DOI] [PubMed] [Google Scholar]
  26. Robey E., Itano A., Fanslow W. C., Fowlkes B. J. Constitutive CD8 expression allows inefficient maturation of CD4+ helper T cells in class II major histocompatibility complex mutant mice. J Exp Med. 1994 Jun 1;179(6):1997–2004. doi: 10.1084/jem.179.6.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Scollay R., Smith J., Stauffer V. Dynamics of early T cells: prothymocyte migration and proliferation in the adult mouse thymus. Immunol Rev. 1986 Jun;91:129–157. doi: 10.1111/j.1600-065x.1986.tb01487.x. [DOI] [PubMed] [Google Scholar]
  28. Shortman K., Vremec D., Egerton M. The kinetics of T cell antigen receptor expression by subgroups of CD4+8+ thymocytes: delineation of CD4+8+3(2+) thymocytes as post-selection intermediates leading to mature T cells. J Exp Med. 1991 Feb 1;173(2):323–332. doi: 10.1084/jem.173.2.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Springer T., Galfrè G., Secher D. S., Milstein C. Monoclonal xenogeneic antibodies to murine cell surface antigens: identification of novel leukocyte differentiation antigens. Eur J Immunol. 1978 Aug;8(8):539–551. doi: 10.1002/eji.1830080802. [DOI] [PubMed] [Google Scholar]
  30. Tomonari K. A rat antibody against a structure functionally related to the mouse T-cell receptor/T3 complex. Immunogenetics. 1988;28(6):455–458. doi: 10.1007/BF00355379. [DOI] [PubMed] [Google Scholar]
  31. Wilson A., D'Amico A., Ewing T., Scollay R., Shortman K. Subpopulations of early thymocytes. A cross-correlation flow cytometric analysis of adult mouse Ly-2-L3T4-(CD8-CD4-) thymocytes using eight different surface markers. J Immunol. 1988 Mar 1;140(5):1461–1469. [PubMed] [Google Scholar]
  32. van Meerwijk J. P., Germain R. N. Development of mature CD8+ thymocytes: selection rather than instruction? Science. 1993 Aug 13;261(5123):911–915. doi: 10.1126/science.8102208. [DOI] [PubMed] [Google Scholar]
  33. von Boehmer H., Swat W., Kisielow P. Positive selection of immature alpha beta T cells. Immunol Rev. 1993 Oct;135:67–79. doi: 10.1111/j.1600-065x.1993.tb00644.x. [DOI] [PubMed] [Google Scholar]

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